Cannabinoid CB1 receptors mediate the CNS effects of delta9-tetrahydrocannabinol (THC), the main psychoactive constituent in marijuana, and the endogenous cannabinoids. This system plays a role in drug abuse, and has therapeutic potential for treatment of nausea, appetite disorders, muscle spasticity and chronic pain, neurodegenerative diseases and mood disorders. However, marijuana/THC have side effects, including sedation, impairment of coordination and short-term memory, and abuse liability, which limits their utility. A better understanding of mechanisms that regulate CB1 receptors could lead to improved strategies to target this system, including the potential to selectively target receptor interaction with regulatory proteins. The proposed project will investigate the function of cannabinoid receptor-interacting protein 1a (CRIP1a) using a null mouse model. CB1 receptors are G-protein-coupled receptors that inhibit synaptic neurotransmission. Our published and preliminary data in cell models co-expressing CRIP1a with CB1 receptors indicate that CRIP1a inhibits both basal (constitutive) and agonist-induced G-protein activation by CB1 receptors without affecting receptor expression levels. We propose to investigate the effects of genetic deletion of CRIP1a on biological phenotype, including weight gain, body temperature, motor activity and coordination, anxiety and pain sensitivity. We will then examine effects of CRIP1a deletion on the pharmacological actions of THC in vivo, and on CB1 receptor expression and activation of G-proteins in CNS regions associated with cannabinoid effects. CRIP1a is postulated to negatively regulate CB1 receptors, so we will test the hypothesis that CRIP1a null mice will display a phenotype that could: 1) mimic the administration of THC (weight gain, hypothermia, anxiolysis, hypolocomotion, reduced coordination, antinociception) and/or 2) enhance the pharmacodynamic potency or efficacy of THC. We further will test the hypothesis that these effects will be associated with enhancement of CB1 receptor-mediated G-protein activity in specific CNS regions, and predict there will be CNS region-specific differences in the effects of CRIP1a deletion corresponding to different effects on behavior and in vivo sensitivity to THC.